Synthesis and conformational analysis of cyclic pentapeptide endothelin antagonists

Two endothelin antagonists cyclo(d‐Leu‐d‐Val‐Pro‐d‐Asp‐Trp) (IPI‐147), and cyclo(d‐Trp‐d‐Asp‐Ac3c‐d‐Val‐Leu) (IPI‐725) have been synthesized. Their solution conformations have been studied in aqueous solution by NMR spectroscopy and dynamics simulation. Activity studies show that IPI‐725 is a strong ETA antagonist, while IPI‐147 is a weak ETA antagonist. Comparison of the solution conformations of these two ETA antagonists suggests that the difference in their activities results from their structural differences. IPI‐147 contains a type II β‐turn with a hydrogen bond between NH of d‐Val and the C = O of d‐Asp. IPI‐725, on the other hand, contains two turns, a type II β‐turn with a hydrogen bond between NH of d‐Asp and C=O of d‐Val, as well as a γ‐turn with a hydrogen bond formed between d‐Val NH and d‐Asp carbonyl group. Therefore IPI‐147 appears to be more flexible than IPI‐725. Although both γ‐turns contain the same residues, their orders in the turn are reversed. The β‐turn in IPI‐725 is formed with d‐Val:Leu:d‐Trp:d‐Asp, while in IPI‐147, the β‐turn is formed with d‐Asp:Trp:d‐Leu:d‐val. The activities and solution conformations of IPI‐147 and IPI‐725 were also compared with BQ‐123 [Cyclo(d‐Trp‐d‐Asp‐Pro‐d‐Val‐Leu)], a well characterized, highly potent endothelin antagonist. © Munksgaard 1996.